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Metformin
Brand Names	Glucophage®, Glucophage XR®, Riomet®
Drug Class	Biguanide
Primary Indications	Type 2 Diabetes
Route(s)	Oral
Onset	Days
Duration	12–24 hours
Metabolism	None
Half-life	~6 hours
Elimination	Renal
Pregnancy	Generally safe
Renal Adjustment	Yes
Hepatic Adjustment	Caution
Black Box Warning	Yes
Controlled	No
FDA Approval	1994

Metformin (Glucophage®)

Endocrine Common First-line Black Box

Overview

Metformin is a biguanide and first-line pharmacologic therapy for Type 2 Diabetes. It lowers glucose primarily by reducing hepatic glucose production and improving insulin sensitivity without increasing insulin secretion.

It carries minimal hypoglycemia risk and is weight-neutral to modestly weight-reducing.

Mechanism of Action

Activates AMP-activated protein kinase (AMPK)
Decreases hepatic gluconeogenesis
Improves peripheral insulin sensitivity
Decreases intestinal glucose absorption (minor effect)

Net effect:

↓ Fasting plasma glucose
↓ A1c (~1–1.5%)
No stimulation of insulin secretion

Indications

Type 2 Diabetes
Polycystic Ovary Syndrome (off-label)
Prediabetes (high-risk patients)

Black Box Warning

Risk of Lactic Acidosis

Rare but potentially fatal
Increased risk in:
- Severe renal impairment
- Advanced liver disease
- Hypoxia
- Acute illness / dehydration

Contraindications

Absolute:

eGFR < 30 mL/min/1.73m²
Acute metabolic acidosis

Relative:

eGFR 30–45 (dose reduction)
Advanced hepatic failure
Severe dehydration

Dosing

Initial:

500 mg once or twice daily

Titration:

Increase by 500 mg weekly as tolerated

Typical:

1500–2000 mg/day

Max:

2550 mg/day (IR)
2000 mg/day (XR)

Renal dosing:

eGFR 30–45 → reduce dose
eGFR <30 → contraindicated

Pharmacokinetics

Absorption:

~50–60%

Protein binding:

Minimal

Metabolism:

None

Half-life:

~6 hours (IR)

Elimination:

Renal (unchanged)

Extended-release formulations:

Reduced GI side effects

Adverse Effects

Common:

GI upset
Diarrhea
Metallic taste

Long-term:

Vitamin B12 deficiency

Serious:

Lactic acidosis (rare)

Drug Interactions

Contrast media (temporary hold recommended)
Cimetidine (reduced renal clearance)
Other nephrotoxic agents

Monitoring

A1c every 3–6 months
Renal function (eGFR)
Vitamin B12 (long-term use)

Clinical Pearls

First-line therapy for most patients with Type 2 Diabetes
Does NOT cause hypoglycemia alone
Weight neutral to mild weight loss
Hold during acute illness or before iodinated contrast

Comparison Within Class

Metformin is the only widely used biguanide in clinical practice.

Compared to:

Sulfonylureas → no hypoglycemia
GLP-1 Receptor Agonists → less weight loss
SGLT2 Inhibitors → no HF/CKD benefit